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United States Patent |
5,334,718
|
Thomas
,   et al.
|
August 2, 1994
|
Chemical process and intermediates used therein
Abstract
The invention provides a novel chemical process for the manufacture of
certain imidazo[4,5-b]pyridine derivatives of the formula I wherein
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the various meanings defined
herein, and their non-toxic salts, which are angiotensin II inhibitors.
The process involves the removal of an electron-deficient phenyl group or
a pyridyl or pyrimidyl group from a compound of the formula II as defined
herein. Certain of the intermediates are novel and are provided as a
further feature of the invention.
Inventors:
|
Thomas; Andrew P. (Congleton, GB2);
Martin; David M. G. (Stockport, GB2);
Lee; Stanley A. (Macclesfield, GB2);
Powell; Lyn (Macclesfield, GB2)
|
Assignee:
|
Zeneca Limited (London, GB2)
|
Appl. No.:
|
007930 |
Filed:
|
January 25, 1993 |
Foreign Application Priority Data
| Jan 28, 1992[GB] | 9201715.1 |
Current U.S. Class: |
546/118; 544/328; 544/331 |
Intern'l Class: |
C07D 471/04 |
Field of Search: |
546/118
544/328,331
|
References Cited
Foreign Patent Documents |
2024137 | Mar., 1991 | CA.
| |
399731 | Nov., 1990 | EP.
| |
400974 | Dec., 1990 | EP.
| |
420237 | Apr., 1991 | EP.
| |
426021 | May., 1991 | EP.
| |
434038 | Jun., 1991 | EP.
| |
495626 | Jul., 1992 | EP.
| |
Other References
G. Bianchetti, et al., "Distacco per Idrazinolisi del Gruppo
2,4-Dinitrofenilico.-Nota II. Idrazinolisi di
1-(2,4-dinitro)-fenil-v-triazoli e-tetrazoli" Gazz. Chim. Ital., 1964, 94,
340-350.
|
Primary Examiner: Dentz; Bernard
Attorney, Agent or Firm: Cushman, Darby & Cushman
Claims
What we claim is:
1. A process for the manufacture of an imidazo [4,5-b]pyridine of the
formula I
##STR6##
or a physiologically acceptable salt thereof, wherein R.sup.1 is
(1-6C)alkyl; R.sup.2 is hydrogen or halogeno; and R.sup.3 and R.sup.4 are
selected from hydrogen, halogeno, (1-6C)alkyl, (1-6C)alkoxy, hydroxymethyl
and hydroxy; which is characterised in that a compound of the formula II
##STR7##
wherein P.sup.1 is an electron-deficient phenyl group or is a pyridyl or
pyrimidyl group, is reacted with a base selected from an alkali metal
hydroxide, (1-12C)alkanolate, (1-12C)alkanethiolate, phenolate,
thiophenolate and diphenylphosphide, wherein any phenyl ring of the latter
three groups may optionally bear a (1-4C)alkyl, (1-4C)alkoxy or halogeno
substituent; whereafter: when a physiologically acceptable salt of a
compound of formula I is required, it is obtained by reaction with the
appropriate acid or base affording a physiologically acceptable ion, or by
any other conventional salt formation procedure; and when an optically
active form of a compound of formula I is required, the process is carried
out with an optically active form of the starting material of formula II,
or a racemic form of a compound of formula I is resolved using a
conventional procedure; and wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
P.sup.1 have any of the meanings defined above.
2. A process as claimed in claim 1 wherein, in the starting material of
formula II, P.sup.1 is a phenyl group bearing 1, 2 or 3
electron-withdrawing groups independently selected from halogeno, nitro,
cyano, trifluoromethyl, di(1-4C)alkylaminosulphonyl or (1-4C)
alkylsulphonyl.
3. A process as claimed in claim 1 wherein, in the starting material of
formula II, P.sup.1 is 4-nitrophenyl.
4. A process as claimed in claim 1 wherein the base is selected from sodium
hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide,
sodium ethoxide, potassium propoxide, sodium butoxide, potassium butoxide,
sodium methanethiolate, potassium methanethiolate, sodium ethanethiolate,
potassium ethanethiolate, sodium propanethiolate, potassium
propanethiolate, sodium butanethiolate, potassium butanethiolate, sodium
phenolate and potassium phenolate, sodium thiophenolate and potassium
thiophenolate, the phenyl ring of which last four bases being
unsubstituted or bearing a methyl, ethyl, methoxy, ethoxy, fluoro, chloro,
bromo or iodo group.
5. A process as claimed in claim 1 wherein the base is selected from an
alkali metal alkanethiolate, an alkali metal alkanolate and an alkali
metal thiophenolate.
6. A process as claimed in claim 1 wherein the base is an alkali metal
alkanethiolate and is generated in situ from the corresponding alkanethiol
with an alkali metal hydride or alkanolate.
7. A process as claimed in claim 5 or 6 wherein the reaction is carried out
at a temperature in the range 0.degree. to 30.degree. C.
8. A process as claimed in claim 1 wherein from 1 to 2.5 equivalents of
base are used.
9. A process as claimed in claim 1 wherein N-methylpyrrolidone is present
as solvent or diluent.
10. A process as claimed in claim i for the preparation of an
imidazo[4,5-b]pyridine of the formula I selected from
2-butyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-methyl]-3H-imidazo-[4,5-b]
pyridine and
2-ethyl-5,7-dimethyl-3-[(2'-(lH-tetrazol-5-yl)biphenyl-4yl)methyl]-3H-imid
azo[4,5-b]pyridine), or of a physiologically acceptable salt thereof.
11. A compound of the formula II
##STR8##
in either a racemic or optically active form; wherein P.sup.1 is an
electron-deficient phenyl group or is a pyridyl or pyrimidyl group; and
wherein R.sup.1 is (1-6C)alkyl; R.sup.2 is hydrogen or halogeno; and
R.sup.3 and R.sup.4 are selected from hydrogen, halogeno, (1-6C) alkyl,
(1-6C) alkoxy, hydroxymethyl and hydroxy.
Description
This invention concerns a novel chemical process for the production of
certain imidazo[4,5-b]pyridine derivatives, which derivatives possess
pharmacologically useful properties in antagonising at least in part one
or more of the actions of substances known as angiotensins, and in
particular of that known as angiotensin II (hereinafter referred to as
"AII"). The invention also concerns various derivatives which are valuable
chemical intermediates, for example for use in the abovementioned process.
The angiotensins are key mediators of the renin-angiotensin-aldosterone
system, which is involved in the control of homeostasis and
fluid/electrolyte balance in many warm-blooded animals, including man. The
angiotensin known as AII is produced by the action of angiotensin
converting enzyme (ACE) from angiotensin I, itself produced from the blood
plasma protein angiotensinogen by the action of the enzyme renin. All is a
potent spasmogen especially in the vasculature and is known to increase
vascular resistance and blood pressure. In addition, the angiotensins are
known to stimulate the release of aldosterone and hence result in vascular
congestion and hypertension via sodium and fluid retention mechanisms.
Compounds which antagonise one or more of the actions of AII are useful
for the reduction or prevention of these effects produced by the action of
AII. There remains a continuing need for alternative AII antagonists and
for effective synthetic procedures for their production such as that
provided by this invention.
In our European Patent Application, Publication No. 399,731 there is
described a series of imidazo[4,5-b]pyridines which possess AII antagonist
properties and which includes compounds of the formula I (set out
hereinafter, together with the other chemical formulae identified by Roman
numerals) wherein R.sup.1 is (1-6C)alkyl; is R.sup.2 is hydrogen or
halogeno; and R.sup.3 and R.sup.4 are selected from hydrogen, halogeno,
(1-6C)alkyl, (1-6C)alkoxy, hydroxymethyl and hydroxy; and physiologically
acceptable salts thereof. Particular values for R.sup.1 (or for R.sup.3 or
R.sup.4 when either is alkyl) include, for example, methyl, ethyl, propyl
and butyl. Particular values for R.sup.2 include, for example, hydrogen,
fluoro, chloro and bromo, or which hydrogen is generally preferred.
Particular values for R.sup.3 or R.sup.4 when it is alkoxy include, for
example, methoxy and ethoxy, and when it is halogeno include, for example,
fluoro, chloro and bromo. Preferred compounds disclosed in said European
application include:
2-butyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4,5-b]pyr
idine;
2-butyl-7-methyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[
4,5-b]pyridine;
2-butyl-5-methyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[
4,5-b]pyridine;
2-butyl-7-chloro-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-imidazo[4
,5-b]pyridine; and
2-butyl-6-(hydroxymethyl)-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imi
dazo[4,5-b]pyridine;
and the physiologically acceptable salts thereof.
In addition, European Patent Application, Publication No. 400974 discloses
other imidazo[4,5-b]pyridines which are AII antagonists. Certain of these
compounds are within the group of compounds of formula I defined above.
One such compound which is of particular interest as an AII antagonist is
the compound:
2-ethyl-5,7-dimethyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imi
dazo-[4,5-b]pyridine; or a physiologically acceptable salt thereof.
We have now discovered a particularly effective process for the manufacture
of the above mentioned imidazo[4,5-b]pyridine AII antagonists and this is
the basis of our invention.
According to the invention there is provided a process for the manufacture
of an imidazo[4,5-b]pyridine of the formula I defined above, or a
physiologically acceptable salt thereof, which comprises reaction of a
compound of the formula II wherein P.sup.1 is an electron-deficient phenyl
group or is a pyridyl or pyrimidyl group, and R.sup.1, R.sup.2, R.sup.3
and R.sup.4 have any of the meanings defined above, with a base selected
from an alkali metal hydroxide, (1-12C)alkanolate, (1-12C)alkanethiolate,
phenolate, thiophenolate and diphenylphosphide, wherein any phenyl ring of
the latter three groups may optionally bear a (1-4C)alkyl, (1-4C)alkoxy or
halogeno substituent.
A particular value for P.sup.1 when it is an electron-deficient phenyl
group includes, for example, a phenyl group bearing 1, 2 or 3
electron-withdrawing groups independently selected from halogeno
(typically chloro or bromo), nitro, cyano, trifluoromethyl,
di(1-4C)alkylaminosulphonyl (such as dimethylaminosulphonyl or
diethylaminosulphonyl) and (1-4C)alkylsulphonyl (such as methylsulphonyl
or ethylsulphonyl).
Suitable bases include, by way of example:
for an alkali metal hydroxide: sodium or potassium hydroxide;
for an alkali metal alkanolate: an alkali metal (1-8C)alkanolate, for
example an alkali metal (1-4C)alkoxide, such as sodium or potassium
methoxide, ethoxide, propoxide or butoxide;
for an alkali metal alkanethiolate: an alkali metal (1-8C)alkanethiolate,
for example an alkali metal (1-4C)alkanethiolate such as sodium or
potassium methanethiolate, ethanethiolate, propanethiolate or
butanethiolate;
for a phenolate or thiophenolate: the sodium or potassium salt of phenol,
thiophenol, or a phenol or thiophenol bearing a methyl, ethyl, methoxy,
ethoxy, fluoro, chloro, bromo or iodo group.
A particular value for an optional substituent on a phenyl group of an
alkali metal phenolate, thiophenolate or diphenylphosphide, when it is
alkyl is, for example, methyl or ethyl; when it is alkoxy is, for example,
methoxy or ethoxy; and when it is halogeno is, for example, fluoro, chloro
or bromo.
A preferred value for P.sup.1 is, for example, a nitrophenyl group or a
4-pyridyl, 4-cyanophenyl, 4-dimethylaminosulphonyl, 4-methylsulphonyl or
3-cyano-4-trifluoromethylphenyl group. Of these values, 4-nitrophenyl is
especially preferred.
A particularly preferred base is an alkali metal alkanethiolate such as
sodium or potassium propanethiolate, an alkali metal alkanolate such as
sodium or potassium methoxide or ethoxide, or an alkali metal
thiophenolate such as sodium or potassium 4-fluorothiophenolate.
It will be appreciated that when the base is an alkali metal alkanolate,
alkanethiolate, phenolate, thiophenolate or diphenylphosphide, it may
conveniently be generated in situ from the corresponding alkanol,
alkanethiol, phenol, thiophenol or diphenylphosphine with a suitable
alkali metal base such as an alkali metal hydride, for example, lithium,
potassium or sodium hydride. Alternatively, when an alkali metal
alkanolate is used, it may be convenient to employ the base as a solution
in the corresponding alcohol (for example a solution of sodium methoxide
in methanol). When an alkanethiolate is used as the base, this may also be
generated in situ from the corresponding alkanethiol with an alkali metal
alkanolate (for example sodium methoxide, which itself may be in the form
of a solution of sodium methoxide in methanol). The amount of base used in
the process is generally 1 equivalent or more, for example from 1 to 12
equivalents may be used, preferably from 1 to 2.5 equivalents.
The process is generally carried out in a suitable inert organic solvent or
diluent, for example, a polar solvent such as N,N-dimethylformamide or
N-methylpyrrolidone. Alternatively, an alkanol such as methanol or ethanol
may be used, for example, when an alkali metal hydroxide or alkoxide such
as sodium or potassium hydroxide, methoxide or ethoxide is employed as
base.
The process is generally carried out at a temperature in the range, for
example, -30.degree. C. to 80.degree. C. It will be appreciated that the
choice of temperature selected depends on the nature of the base employed.
For example, when an alkali metal alkanethiolate or alkanolate is used, a
temperature in the range of 0.degree. C. to 30.degree. C. (conveniently at
or about ambient temperature) is preferred. Similarly, when an alkali
metal alkoxide is employed as base, the process may conveniently be
performed at or near the boiling point of the corresponding alkanol, for
example at about 40.degree. to 80.degree. C.
The starting materials of the formula II as defined hereinbefore may be
obtained, for example, by alkylation of an imidazo[4,5-b]pyridine of the
formula III wherein R.sup.1, R.sup.3 and R.sup.4 have any of the meanings
defined above, with a compound of the formula IV wherein P.sup.1 and
R.sup.2 have any of the meanings defined hereinbefore and Hal. stands for
a halogeno group such as chloro, bromo or iodo.
The alkylation may be carried using conditions already well known in the
art for analogous alkylations. Thus, it may be performed in the presence
of a suitable base, for example, an alkali metal alkoxide such as sodium
methoxide or sodium ethoxide, an alkali metal carbonate such as sodium
carbonate or potassium carbonate, or an alkali metal hydride such as
sodium hydride or an organic base such as diisopropylethylamine and in a
solvent or diluent, for example, a (1-4C)alkanol such as methanol or
ethanol when an alkali metal alkoxide is used, or in a polar solvent such
as N,N-dimethylformamide or N-methylpyrrolidone and at a temperature in
the range, for example, 10.degree.-100.degree. C. Alternatively, a
quaternary ammonium hydroxide may be used in a mixture of an aqueous or
non-aqueous solvent such as water and dichloromethane. In some cases, the
alkylation may produce a mixture containing the desired compound of
formula II together with one or two isomers thereof, requiring
purification of the intially formed alkylation mixture by a conventional
procedure, for example by fractional crystallisation or chromatography.
The starting imidazo[4,5-b]pyridines may themselves be obtained by known
procedures, for example, as described in the aforementioned European
Patent Applications. Similarly, the compounds of formula IV may be
obtained from the appropriate 2-bromobenzoic acid and amine of the formula
P.sup.1.NH.sub.2, for example, as shown in Scheme 1 hereinafter (for
Hal.=bromo).
Whereafter, when a physiologically acceptable salt of a compound of formula
I is required, it may be obtained, for example, by reaction with the
appropriate base affording a physiologically acceptable cation, or with
the appropriate acid affording a physiologically acceptable anion, or by
any other conventional salt formation procedure.
Further, when an optically active form of a compound of formula I is
required, for example when one or more of R.sup.1, R.sup.2 and R.sup.3 is
an asymmetrically substituted alkyl, the aforesaid process may be carried
out using the appropriate optically active form of the starting material
of formula II. Alternatively, a racemic form of a compound of formula I
may be resolved using a conventional procedure.
It will be appreciated that an alternative process variant of the present
invention involves the use of a starting material of formula I in which
the group P.sup.1 is attached to the 2-nitrogen atom of the tetrazole ring
rather than to the 1-nitrogen atom as specified hereinabove. The necessary
starting materials for such a process variant may be made by methods well
known in the art for the preparation of structurally analogous compounds.
The process of the invention is particularly advantageous for the
production of the compounds of formula I (and especially of compounds such
as:
2-butyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo-[4,5-b]p
yridine; or
2-ethyl-5,7-dimethyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imid
azo[4,5-b]pyridine or of physiologically acceptable salts thereof, with
high purity, such as is required for their intended pharmaceutical use.
The intermediates of formula II as defined hereinabove are novel and are
provided as a further feature of the invention.
The invention will now be illustrated by the following non-limiting Example
in which, unless otherwise stated:
(i) concentrations and evaporations were carried out by rotary evaporation
in vacuo;
(ii) operations were carried out at room temperature, that is in the range
18.degree.-26.degree. C.;
(iii) yields, where given, are intended for the assistance of the reader
only and are not necessarily the maximum attainable by diligent process
development;
(iv) .sup.1 H NMR spectra were normally determined at 270 MHz in CDCl.sub.3
using tetramethylsilane (TMS) as an internal standard, and are expressed
as chemical shifts (delta values) in parts per million relative to TMS
using conventional abbreviations for designation of major peaks: s,
singlet; m, multplet; t, triplet; br, broad; d, doublet; and
(v) the term "1H-tetrazol-5-yl" is the abbreviated version of
"1H-1,2,3,4-tetrazol-5-yl".
EXAMPLE 1
A solution of sodium methoxide in methanol (30% w/v, 4 mL) was added to a
solution of
2-ethyl-5,7-dimethyl-3-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4
-yl)methyl]-3H-imidazo[4,5-b]pyridine (A) (1.0 g) in methanol (20 mL) and
the mixture was heated under reflux for 18 hours. The mixture was cooled
to ambient temperature and solvent was removed by evaporation. The residue
was dissolved in water (50 mL) and the solution was extracted with ether
(2.times.50 mL). The aqueous layer was separated and adjusted to pH 5 with
1M citric acid solution. The product was collected by filtration and dried
to give
2-ethyl-5,7-dimethyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imi
dazo[4,5-b]pyridine (0.6 g) as a solid, m.p. 175.degree.-177.degree. C.
(decomposition); NMR (d.sub.6 -acetone): 1.26(t, 3H), 2.50(s, 3H), 2.53(s,
3H), 2.76(q, 2H), 5.49(s, 2H), 6.91(s, 1H), 7.07(d, 2H), 7.14(d, 2H),
7.6(m, 3H), 7.75(dd, 1H); mass spectrum (+ve fast atom bombardment (FAB),
DMSO nitrobenzyl alcohol): 410(M+H).sup.+ ; microanalysis, found C, 64.9;
H, 5.6; N, 22.0%; C.sub.24 H.sub.23 N.sub.7.2.0H.sub.2 O requires: C,
64.7; H, 6.0; N, 22.0%.
The starting material A was prepared as follows:
(i) Thionyl chloride (120.5 g) was added to a stirred mixture of
2-bromobenzoic acid (194.0 g) in toluene (500 mL) and
N,N-dimethylformamide (DMF) (5 mL) and the mixture heated at 80.degree. C.
for 4 hours. The solution was cooled to 20.degree. C. and added slowly to
a solution of 4-nitroaniline (133.1 g) in toluene (500 mL) and
N-methylpyrrolidone (NMP) (120 mL), maintaining the temperature of the
reaction mixture between 20.degree.-25.degree. C. The reaction mixture was
then stirred for 24 hours, during which time a solid precipitated. Water
(360 mL) was added with rigorous stirring. The suspended solid was
collected by filtration, and washed successively with water, toluene and
acetonitrile to give 2-bromo-N-(4-nitrophenyl)benzamide (B) as a solid, in
87% yield; m.p. 200.degree.-202.degree. C.; NMR (d.sub.6 -DMSO):
7.4-7.8(m, 7H), 8.0(d, 2H), 8.3(d, 2H), 11.5(br s, 1H). This material was
used without further purification in step (ii).
(ii) Triethylamine (1.04 g; 10.38 mM) was added to a mixture of amide B
(3.0 g; 9.35 mM) in acetonitrile (12 mL) and DMF (0.189 g; 2.58 mM) and
the mixture was stirred for 90 minutes. Thionyl chloride (1.44 g; 12.14
mM) was then added slowly, keeping the reaction temperature below
25.degree. C. The mixture was stirred for 5 hours at ambient temperature
and then cooled to 10.degree. C. Triethylamine (2.83 g; 8 mM) was then
added, followed by sodium azide (1.33 g; 20.4 mM) and tetrabutylammonium
bromide (0.42 g; 1.3 mM). The mixture was stirred for 2 hours at
10.degree. C. and then allowed to warm to ambient temperature and stirring
continued for 24 hours. The mixture was poured into excess water and the
precipitated solid collected by filtration. The solid was purified by
trituration with a hot mixture of ethyl acetate (26 mL), hexane (2.6 mL)
and triethylamine (0.1 mL) to give
5-(2-bromophenyl)-1-(4-nitrophenyl)-1H-tetrazole (C) (2.36 g; 73% yield)
as an off-white solid, m p. 169.degree.-170.degree. C.; NMR (d.sub.6
-acetone; 270 MHz): 7.61-7.86(m, 6H), 8.41(d, 2H); microanalysis, found:
44.8; H, 2.3; N, 20.2; Br, 23.1%.
(iii) A mixture of 4-methylphenyl boronic acid (9.7 g; 71 mM), sodium
carbonate (16.7 g; 158 mM), water (100 mL), methanol (50 mL) and toluene
(50 mL) was heated to 60.degree. C. to give a clear solution. Compound C
(20.0 g; 55 mM) was then added, followed by
tetrakis(triphenylphosphine)palladium (0.3 g; 0.25 mM) and the mixture was
heated under reflux for 3 hours. Toluene (30 mL) was added and the warm
mixture was filtered through diatomaceous earth. The organic phase was
separated and the aqueous phase was extracted with toluene (40 mL). The
combined organic phases were evaporated to give a solid which was
recrystallised from toluene/petroleum ether (100.degree.-120.degree. C.)
(1:1 v/v) to give
5-(4'-methylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (D)(18.7 g; 90%
yield), m.p. 164.degree.-166.degree. C.; NMR (CDCl.sub.3): 2.3(3H, s),
6.45(2 H, d), 6.85(4H, m), 7.38(1H, d), 7.65(2H, m), 7.85(1H, d), 8.0(2H,
d).
(iv) A mixture of compound D (8.0 g; 21 mM), N-bromosuccinimide (4.53 g; 25
mM) and azo(bisisobutyronitrile) (73 mg) in 1,1,1-trichloroethane (methyl
chloroform) (50 mL) was heated under reflux for 4 hours. The mixture was
cooled to ambient temperature, washed with water (3.times.50 mL), and the
suspended solid collected by filtration to give
5-(4'-bromomethylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (E) (7.3
g), m.p. 192.degree.-195.degree. C.; NMR (CDCl.sub.3): 4.4(2H, s),
6.52(2H, d), 6.85(2H, d), 7.07(2H, d), 7.4(1H, d) 7.7 (2H,m), 7.9(1H, d).
(v) 2-Ethyl-5,7-dimethylimidazo[4,5-b]pyridine (obtained as described in
European Patent Application, Publication no. 400974) (2.0 g) was added to
a mixture of potassium carbonate (4 g) and compound E (6.0 g) in
1,2-dimethoxyethane (100 mL). The mixture was heated at 60.degree. C. for
2.5 hours, then cooled to ambient temperature and saturated sodium
chloride solution added. This mixture was extracted with ethyl acetate
(2.times.100 mL) and the combined extracts dried (MgSO.sub.4). Solvent was
removed by evaporation and the residue was purified by flash
chromatography eluting with ethyl acetate/hexane (1:1 v/v) to give
2-ethyl-5,7-dimethyl-3-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4
-yl)methyl]-3H-imidazo[4,5-b]pyridine (A) (3.1 g) as a gum; NMR
(CDCl.sub.13): 1.40(t, 3H), 2.64(s, 3H), 2.68(s, 3H), 2.86(q, 2H), 5.39(s,
1H), 6.47(d, 2H), 6.71(m, 4H), 6.79(d, 2H), 6.97(s, 1H), 7.35(m, 1H),
7.65(m, 2H), 7.75(m, 2H), 7.85(m, 1H); mass spectrum (+ve FAB,
DMSO/nitrobenzyl alcohol): 531(M+H).sup.+.
##STR1##
Reaction conditions:
(a) SOCl.sub.2, DMF, toluene, 80.degree. C.; then add to p.sup.1.NH.sub.2,
toluene, N-methylpyrrolidone at ambient temperature
(b)
(i) ET.sub.3 N, CH.sub.3 CN, DMF;
(ii) SOCl.sub.2, 10.degree. C.; and
(iii) Et.sub.3 N, NaN.sub.3, tetrabutylammonium bromide, 10.degree. C. to
ambient temperature
(c) Add product of product from (b) and (Ph.sub.3 P).sub.4 Pd to pre-formed
solution of (4-CH.sub.3)phenylboronic acid, Na.sub.2 CO.sub.3, MeOH, and
toluene, 60.degree. C.; then heat under reflux
(d) N-bromosuccinimide, azo(bisisobutyronitrile), CH.sub.3 CCl.sub.3
______________________________________
CHEMICAL
FORMULAE
______________________________________
##STR2## I
##STR3## II
##STR4## III
##STR5## IV
______________________________________
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